Amino acid synthesis



v Patented Oct. 30, 1945 N T DESTATE ACID s mmers ,Carl E. Sohweitzeif', Newport; Delsassirnor to E. I.

du Pont de Neinours & Company, Wilmington, D et, a corporation Delaware No Drawing. Application outta-2.194s,-

T Serial No. 504.795

fs clause (cl. a e-s34) This inventlonrelates to'thesynthesisoiamino acids, and particularly -tothe synthesls-ot-arnino acids from amino nitriles.

Amino acids have been. prepared in thepa st by several methods. A study orthe various methods of preparing amino-acetic acid is reported in Organic Syntheses}? 298-301, Gillman and John Wiley and Sons, v enearninoacetonitrile-and aminoac etonitrile have been 'saponifled with solutions of droxides to form solutionsot precipitating thealka'li or sulfate.

The salts of amino acids-,exhibit' uniquebeha- W k a @9 1 a bonic' acid. Thus. when calclum aminoacetate is treated with carbon dioxi'dein aqueoussolutioni under ordinary conditions a slow and partial precipitation of; calcium carbonate occurs. For reavior when treated with sons of economy it would be; desirable ltd liberate amino acids from thei rg-alkali earth metal salts by treatment with carbon dioxide, because the iearthmetal carbonate: 1

CollectiveVolume 1, pages Bla-tt,: .1941, published by j Inc. For example, inethyyI- alkali earth'hy alkali earth metal f salts of aminoacetic acid. Free aminoacetieacid 5 in solution has been liberated from these. saltsby. I I

carbonates thus producedxcould be'converted in a separate step to oxldeor hydroxide, and could be used repeatedly in the-saponification of the amino nitrile. Thisiha's not been possible hitherto, because ofthe slow and incomplete reac tion of carbon di acid.

oxide with the salt of the amino In accordance withthe present l n heuever, aminonitriles are-saponifiedand-thesapom ification products Jere-converted rapidly and quantitatively to the free aqueous amino acid by soluble carbonate is employed,,-the,iamino acid.-

barium, calcium or strontium when-the amino acid salts of these metals are treated j with'carbon dioxide under pressure and moved. suitably by flltrajtlon, and thq'remgi .ms iquor is concentrated'td ohm-the mm-m3 acetic acid.

. -Theamino nitriles which may in 1 invention include the primary, secondary and tertiary: amino nitriles which form. watersoluble salts of alkali earth metals. and which also iurm amino acids which are water solublei. Bincethese solubilities are 'quiteglowwhenfthe total number.

of carbon. atoms in' the. molecule exceeds '8, the

invention is;partlcularly applicable to amino-ni triles having from 2 to 8' carbon'atoms per mole- I .cule. :1 Examples-oi such nitriles are: aminoaceto;v

trile, l i-ethylaminoacetonitrile, -N,N-diethyl-alphavarninopropionitrile and N-hexylaminoaceto .mtriler The saponiflcation may-be carried out with any of the known saponifying agents such as sodium" hydroxide, potassium hydroxide, barium hydroxide. calcium hydroxide, strontiumhydroxide, or lithium hydroxide. It is preferred to use at elevated temperature insoluble carbonates are produced; If ametal hydroxide which yleldsa may beseparated 'i'rom -such carbonate by jfrac .tionalcrystallization.f"Ofthe various saponifytreatment with carbon dioxide. :This is accomplished as a result of the discovery that the amino v acid salts andcarbon ldioxide at'elevated temperatures and pressures do not exhibitthe slow and. partial action which is observed whencarbon dimg agents which may lie-employed,- the most eonvenientfone-to' use is-bariumnydroxide, for, after J theJsaponiflcation andcarbon dioxide treatment therecovered barium carbonate can be converted very readilybyhe'at tothe oxide,' fronj1 which it is possible to prepare a suitable aqueous barium hydroxide saponifying" solution.

oxide is absorbed in the amino acid saltatordi 5 1 nary temperature. and; pressure, butyinstead a! V pheric pressure or below,1but a more rapid rate rapid conversion to the amino acid takes place.-

In accordance with this invention anamino nia trile is saponifled, 'andthe saponification product is treated with carbon dioxideunder superatmos pheric pressure at elevated temperature. In one specificxembodiment aminoacetonitrile is saponifled with a suspensionoi'alkali earth hydroxide,"

and solution of alkali earth salt of aminoacetic acid thus obtained is aaitated withcarbon'dioxide under superatmospheric pressure and elevated temperature, causing a precipitation of alkali earth carbonate. The alkali earth carbonate is I thepractice orthis invention'the saponiflca tion of amino nitrile may-be conducted at atmosv of saponification is attained when the reaction is 7 carried out me. closedvessel at a pressureh'igher than atmospheric and at temperatures abovelqu C; Temperatures of 0 to.-200 (Limay be em- I ployed,but the. preferred range is to C.

Preferably the pressure under which. the saponi-.

. -fication reaction proceeds may be from 1 to 15 v atmospheres. In treating the saponification" product with carbon dioxide, temperatures of from 0 to 200 C. may be employed, but the preierred range is 50 to 100 C. Carbon dioxide ENT, 1 OFFICE hydroxides because pressure during treatment of the saponiflcation product with carbon dioxide may be from 1 to 100 atmospheres, the preferred range being from 30 to 50 atmospheres.

The relative quantities of saponifying agent wide range, but it is convenient to useequivalent amounts or saponifying agent and amino nitrile. A few percent excess of saponifying agent is frequently employed. The amount of water pres-' ent is generally suflicient to dissolve or suspend the saponifying agent, and preferably amounts to from 2 to -times the weight of aminonitrile employed. The amount of carbon dioxide which is allowed to dissolve in or react with the saponiflcation product is generally at least sumcient .to convert the metal initially present'in the saponifying agent to carbonate, although partial or even total conversion to bicarbonate by excess carbon dioxide may also be obtained.

The following examples will serve toillustra'te and amino nitrile employed may vary over a very in greater detail the method of practicing this invention.

Example 1.--Into a boiling solution of 33.3 grams Ba(OH) 2.8H2O'in 150 cc. waterwas added 14.1 grams N-methylamino acetonitrile, and the mixture was heated under reflux with stirring for 1 hour, then without stirring for 4 additional hours. The resulting mixture was transferred to an autoclave wherein it was agitated for 15 min-.

utes at 75 C; with carbon dioxide under 40 at= The mixture was then transferred to an autoclave and heated for 15 minutes at 75 with carbon dioxide at 40 atmospheres pressure. The resulting product was centrifuged, and the aminoacetic acid liquor was removed from the precipitate. The precipitate was washed with warm water, and the washings were added to the aminoacetic acid liquor. This mixture was then concentrated, and several batches of crystals were separated until the volume of mother liquor was only 10 c. c. The total weight of crystalline aminoacetic acid thus obtained was 51.6 grams.

The reaction between carbon dioxide and the salt of amino acid, as described above, may be conducted in any heated, suitable pressure resisting vessel such as a steel, stainless steel, aluminum-lined, silver-lined or glass-lined autoclave, preferably equipped with a stirrer or shaking machine.

The carbonation reaction may be conducted either batchwise or continuously. In the continuous process, which is preferably performed under pressure, carbon dioxide may be introduced either at one point or at several points in the reaction vessel. I

It will be appreciated that several methods for removing salts of carbonic acid from the carbonation product containing amino acid may be employed without deviating from the principle of this invention These methods of separating salts of carbonic acid from such solution include filtration, continuous centrifuging, settling, and

3 the like. While in the preferred procedure it is grams was thus obtained. This was recrystallized from hot water, yielding 6.0 grams N-methylaminoacetic acid; which had a melting point of 204 to 207 C., with decomposition.

Example 2.-Into a boiling solution of 33.3 grams Ba-(OH) aBHzO in 200 cc. water was added, drop by drop, 56 grams aminoacetonitrile. This required 1.5 hours. The mixture was boiled for an additional hour at atmospheric pressure to complete the hydrolysis and to expel ammonia.

The resulting solution of barium aminoacetate was transferred to an autoclave, in which it was processed for 15 minutes with carbon dioxide under 40 atmospheres pressure at 75 C. The slurry thus obtained was centrifuged, and the resulting clear supernatant liquor was drawn oil. The precipitate was washed with warm water three times and each time theprecipitate was separated from the liquor by centrifuging and drawing off the supernatant liquor. The combined clear liquors thus obtained were concentrated to a'v'olume of 100 c. c. by distilling ofl the excess water. Upon cooling this concentrate to 20. 29 grams crystals were obtained. The mother "liquor was then concentrated to 25 0.0.. and an additional 33.5 grams crystals were obtained.

,The mother liquor from this crystallization was further concentrated to 10 c. c. whereupon an additional 6 grams crystals were obtained. Thus not necessary to resort to fractional crystallization, this method, as above noted, is useful when the saponifying agent is sodium hydroxide or other hydroxide which yields a soluble carbonate.

In such instances the. s'aponiflcation product is concentrated by evaporation of solvent until crystals appear. These crystals are removed and the concentration is resumed. These operations are repeated until the volume of mother liquor is very small, and several batches of crystals have been obtained. The intermediate batches are dissolved in a minimum amount of solvent and fractionated again in the same manner. Fractions of like composition are combined for the "refractionations. Ultimatel the amino acid and soluble carbonate are obtained in appreciable yield as the intermediate batches of crystals become smaller and smaller in quantity due to the refractionation. When the saponlfying agent is barium hydroxide, or other hydroxide which yields an insoluble carbonate, 9. clear solution of amino acid is obtained after removal of this insoluble carbonate. Several methods may be employed 1. In a' process for preparing amino acetic acid,

the steps which comprise heating aminoaceto nitrile in water with calcium hydroxide at 0 to- 200 C. and thereafter introducing carbon dioxide into the resulting solution of calcium aminoacetate at 50 to C., under 30 to 50 atmospheres pressure, separating precipitated calcium carbonate from the solution of aminoacetic acid thus obtained and evaporating water from the supernatant liquor, thus forming crystals of aminoacetic acid.

2. In a, process for the preparation of amino acids 0! the formula RNHCHzCOOH, in which R is a member of the class consisting of hydrogen and methyl groups, the step which comprises treating an aqueous solution of an alkali earth metal salt of the said'amino acid with carbon dioxide under superatmospheric pressure, whereby the alkali earth metal is precipitatedas carbonate and free amino acid in solution is liberated.

3. In a process for the preparation of aminoacetic-acid, the step which comprises treating an aqueous solution of an alkali earth metal salt of the said amino acid with carbon dioxide at a temperature within the range of about to 200 C. under a superatmospheric pressure within the range of about 1 to 100 atmospheres, whereby the alkali earth metal is substantially completely precipitated as carbonate and free amino acid is liberated in solution.

droxide.

5. The process set forth in claim 3 in which the alkali earth metal hydroxide is calcium hydroxide.

6. In a process for the preparation of amino acids, the step which comprises treating an aqueous solution of barium salt of N-methyl aminoacetic acid with carbon dioxide at a temperature of about 50 to 100 C. under a pressure of about to atmospheres, whereby the barium is precipitated as carbonate, and N-methyl aminoacetic acid is liberated in solution.

CARL E. SCHWEITZER. 

